P1038: CLINICOPATHOLOGIC AND MOLECULAR CORRELATES OF ORGAN DAMAGE ACROSS THE SPECTRUM OF ADVANCED SYSTEMIC MASTOCYTOSIS
Authors: E. Liang, C. Perkins, R. Lu, H. Shi, S. Dimitrijevic, G. Hoehn, J. Abuel, C. Langford, P. Abidi, L. Fechter, W. Shomali, J. Gotlib
Journal: HemaSphere (2022)

Background: Advanced SM (AdvSM) comprises 3 subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). The patterns of organ damage across the spectrum of AdvSM have not been well characterized. The definition of hematologic and non-hematologic organ damage has evolved from World Health Organization (WHO) C-findings, to organ damage criteria specified by the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG). More recently, modified IWG (mIWG) criteria have been used to define eligible organ damage in trials of AdvSM. Aims: 1) To describe the distribution of organ damage in AdvSM patients (pts) at initial presentation or at time of trial enrollment using WHO, IWG, and mIWG criteria; 2) to evaluate clinicopathologic and molecular correlates of organ damage. Methods: Our cohort included 244 AdvSM pts: 68 pts from our Stanford IRB-approved MPN registry and 176 pts from the phase I EXPLORER (NCT02561988) and phase II PATHFINDER (NCT03580655) studies of avapritinib in AdvSM. Comparisons between continuous and categorial variables were performed using the Wilcoxon rank sum test and the Fisher’s exact test, respectively. The Benjamini and Hochberg method was used to control the false discovery rate in multiple comparisons. Results: Median age at diagnosis was 68 years (range, 24-88) and 146 pts (60%) were male. Forty-one pts (17%) had ASM, 165 (68%) had SM-AHN, and 38 (16%) had MCL. The median number of prior anti-neoplastic therapies was 1 (range, 0-6), with 87 pts (36%) previously treated with midostaurin. Comparison of AdvSM Subtypes: Pts with MCL had the highest transfusion requirement, with 13% and 8% of pts requiring RBC and platelet transfusions, respectively. SM-AHN pts had the highest median alkaline phosphatase (ALP) (214 U/L), while pts with MCL had the largest median liver (2860 cm3) and spleen (1120 cm3) volumes by imaging. Among the two largest SM-AHN subtypes, pts with SM-CMML (n = 72) had a lower ANC (p = 0.02) and tryptase levels (p = 0.04) than pts with MDS/MPN-U (n = 36). Pts with SM-AHN fulfilled the WHO thrombocytopenia criterion (<100 x 109/L) more frequently than MCL and ASM pts, and more WHO hematologic (p = 0.02) and IWG non-hematologic (p = 0.008) criteria than ASM pts. Prior Therapy: Pts who received ≥1 prior anti-neoplastic therapy (compared to none) had greater tryptase levels (p = 0.02) and bone marrow (BM) MC burden (p = 0.03), lower ALP (p = 0.04), and higher likelihood of meeting WHO malabsorption criteria (hypoalbuminemia and/or weight loss) (p = 0.03). Compared to midostaurin-naïve pts, those who had received midostaurin had a greater BM MC burden (p = 0.045), but less frequently met mIWG splenomegaly criteria (p = 0.04) and met fewer WHO non-hematologic criteria (p < 0.001). Mutation Profiles: Compared to pts with KIT D816V only, pts who also had ≥1 SRSF2, ASXL1, or RUNX1 mutations had a lower median hemoglobin (p = 0.02), platelet count (p = 0.02), and greater direct bilirubin (p = 0.005), ALP (p = 0.04), and spleen volume (p = 0.06). They were more likely to fulfill the WHO hypersplenism criterion (p = 0.03) and exhibited more WHO-defined cytopenias (p = 0.006). Image:Summary/Conclusion: In AdvSM, patterns of organ damage reflect disease subtype, prior therapy, and mutation profile beyond KIT D816V (Figure). These data can help inform the clinical heterogeneity of AdvSM patients who are being evaluated for clinical trials which currently require 1 or more organ damage findings defined by the WHO or (m)IWG criteria.